In general terms, the objective of this proposal is to elucidate the molecular mechanisms of steroid hormone dependent gene regulation. This knowledge is crucial for understanding tumorigenic potential of specific hormone receptor cofactors and for the development of novel hormone receptor modulators advancing prevention and treatment of clinical disorder. Specifically, this proposal will investigate targeted histone modification mediated by hormone receptor-coregulator interactions. The specific aims are to determine gene specific, cell type specific, and receptor specific coregulator recruitment associated with selective histone modifications and to identify the causal relationship between histone modification and cofactor participation. The first three aims will be accomplished by using chromatin immunoprecipitation analysis and established cell lines. The last specific aim will be achieved by targeted manipulation of coregulator functions and evaluation of the effects on histone modification as well as gene expression. Finally, the role of selective histone modification will be explored.